Meprin A is an oligomeric zinc metalloproteinase found at the brush border membranes of kidney proximal tubule cells. A variety of studies involving genetics, meprin activity levels, and meprin inhibitor effects in cultured cells and live rodents suggest that meprin A activity plays a key role in the etiology of acute kidney failure. This deadly disease affects over 250,000 Americans each year, with a 60% death rate. The treatment costs for end-stage renal disease are over $12 billion annually in the United States alone. We propose to design and synthesize low nanomolar, small molecule inhibitors of meprin A as the first step in a program aimed at discovering clinically useful agents for the prevention and delay of acute kidney failure. The steps involved are as follows: 1. Assay 50 potential metalloprotease inhibitors with relevant structures for their ability inhibit meprin A and determine the IC50 values. 2. Based on the activity data determine the structure activity relationship (SAR) for this set of inhibitors. 3. Construct 3- dimensional computational models for putative human meprin A/inhibitor complexes by using a homology-derived model of murine meprin A. Using the protein modeling technology at Sapient Discovery, fine-tune this homology model to improve the accuracy of prediction of the IC50 values for the inhibitors. 4. Based on the most active compounds develop a focused virtual library of 500 inhibitor candidates and use docking procedures to rank order the compounds based on predicted activity. 5. Synthesize and screen 30 molecules, including 20 of the most promising molecules in this virtual library. Phase I will be successfully completed when at least one inhibitor of meprin A is discovered with IC50 = 20 nM and a molecular weight of less than 600 Daltons. The considerable experience in the rational design, synthesis and screening of metalloproteinase inhibitors at Sapient Discovery will be directly applicable to the proposed discovery of potent meprin A inhibitors. Each year, acute kidney failure affects more than 250,000 Americans, causing over 150,000 deaths at a cost exceeding 12 billion dollars. We aim to develop drug candidates that block meprin A, an enzyme that plays a key role in acute kidney failure using an innovative structure-based procedure
